1. Filed of the Invention
The present invention relates to a cyclopentanone or cyclopentanone derivative intermediate compound for a 2-substituted-2-cyclopentenone compound having superior pharmacological activities, such as an anticancer activity and bone formation activity.
2. Description of the Related Art
A prostaglandin is a compound having specific biological activities, such as a platelet agglutination inhibitory activity and a vasodepressor activity, and is a useful naturally occurring substance which is now used in the medical field as a therapeutic agent for diseases of the peripheral cardiovascular system. Among the prostaglandins, prostaglandin A compounds are known as a prostaglandin having a double bond in its cyclopentane ring. For example, European Unexamined Patent Publication No. 0106576 (publication date: Apr. 25, 1984) discloses 4,5-substituted-2-cyclopentenone compounds embracing the prostaglandin A compounds, which include 5-alkylidene-4-substituted-2-cyclopentene compounds represented by the following formula: ##STR2## wherein W stands for a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms; and
Y stands for a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, PA1 R.sup.5 represents a hydrogen atom, or a substituted or unsubstituted (i) aliphatic hydrocarbon group having 1 to 10 carbon atom or (ii) alicyclic hydrocarbon group having 4 to 10 carbon atoms; PA1 X represents a hydrogen atom or a group --OR.sup.4 where R.sup.4 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an acyl group having 2 to 7 carbon atoms, tri(C.sub.1 -C.sub.7) hydrocarbon silyl group, or a group capable of forming an acetal bond together with the oxygen atoms attached to the R.sup.4; and PA1 Y represents a hydrogen atom or a group --CH(OH)--R.sup.2 where R.sup.2 is a substituted or unsubstituted (i) aliphatic hydrocarbon group having 1 to 10 carbon atoms, (ii) alicylic hydrocarbon group having 4 lo 10 carbon atoms, (iii) aromatic hydrocarbon group having 6 to 10 carbon atoms or (iv) heterocyclic group having 1 to 9 carbon atoms; with the proviso that, when X is a hydrogen atom Y is a group --CH(OH)--R.sup.2 and that, when X is a group --OR.sup.4, Y is a hydrogen atom. PA1 R.sup.30 represents a hydrogen atom or a substituted or unsubstituted (i) aliphatic hydrocarbon group having 1 to 10 carbon atoms, (ii) alicyclic hydrocarbon group having 4 to 10 carbon atoms or (iii) aromatic hydrocarbon group having 6 to 10 carton atoms; PA1 R.sup.4 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an acyl group having 2 to 7 carbom atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, a tri(C.sub.1 -C.sub.7) hydrocarbon silyl group or a group capable of forming an acetal bond together with the oxygen atom attached to the R.sup.4 ; and PA1 R.sup.5 represents a hydrogen atom or a substituted or unsubstituted (i) aliphatic hydrocarbon group having 1 to 10 carbon atoms or (ii) alicyclic hydrocarbon group having 4 to 10 carbon atoms; with the proviso that both R.sup.5 and R.sup.30 are not a hydrogen atom at the same time. PA1 R.sup.2 stands for a substituted or unsubstituted (i) aliphatic hydrocarbon group having 1 to 10 carbon atoms, (ii) alicyclic hydrocarbon group having 4 to 10 carbon atoms, (iii) aromatic hydrocarbon group having 6 to 10 carbon atoms or (iv) heterocyclic group having 1 to 9 carbon atoms; PA1 R.sup.3 stands for a hydrogen atom or a substituted or unsubstituted (i) aliphatic hydrocarbon group having 1 to 10 carbon atoms, (ii) alicyclic hydrocarbon group having 4 to 10 carbon atoms or (iii) aromatic hydrocarbon group having 6 to 10 carbon atoms; PA1 X stands for a hydrogen atom, or --OR.sup.4 (wherein R.sup.4 stands for a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an acyl group having 2 to 7 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, a tri(C.sub.1 -C.sub.7) hydrocarbon silyl group or a group capable of forming an acetal bond together with the oxygen atom attached to the R.sup.4), provided that X is absent when R.sup.3 is bonded to the carbon atom bonding thereto through a double bond; PA1 5 stands for a hydrogen atom, or a substituted or unsubstituted (i) aliphatic hydrocarbon group having 1 to 10 carbon atoms or (ii) an alicyclic hydrocarbon group having 4 to 10 carbon atoms; PA1 B stands for a hydrogen atom when A stands for a hydrogen atom, a hydroxyl group, an acyloxy group having 2 to 7 carbon atoms, an alkoxycarbonyloxy group having 2 to 5 carbon atoms, a sulfonyloxy group having 1 to 7 carbon atoms or ##STR9## or A and B are combined with each other to form a bond line; m and n, which may be the same or different from each other, stand for 0, 1 or 2. PA1 A.sup.2 stands for a hydrogen atom, a hydroxyl group, an acyloxy group having 2 to 7 carbon atoms, an alkoxycarbonyloxy group having 2 to 5 carbon atoms or a sulfonyloxy group having 1 to 7 carbon atoms; PA1 X.sup.1 stands for a hydrogen atom or OR.sup.4 (wherein R.sup.4 is as defined above). When the R.sup.3 is attached to the carbon atom of the cyclopentene skeleton through a double bond and X is absent, the above-described formula (I) represents 2-substituted-2-cyclopentenones represented by the following formula (I"): ##STR16## wherein A, B, R.sup.1, R.sup.2, R.sup.5, n and are as defined above; R.sup.31 and R.sup.32 which may be the same or different from each other stand for a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 9 carbon atoms, alicyclic hydrocarbon group having 4 to 10 carbon atoms or aromatic hydrocarbon group having 6 to 10 carbon atoms, or a group wherein the R.sup.31 and R.sup.32 are combined with each other to form an alicyclic hydrocarbon group having 4 to 10 carbon atoms. PA1 R.sup.20 and R.sup.21 each stand for a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, alicyclic hydrocarbon group having 4 to 10 carbon atoms, aromatic hydrocarbon group having 6 to 10 carbon atoms or heterocyclic group having 1 to 9 carbon atoms; PA1 R.sup.300 and R.sup.301 each stand for a hydrogen atom or a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, alicyclic hydrocarbon group having 4 to 10 carbon atoms or aromatic hydrocarbon group having 6 to 10 carbon atoms; PA1 R.sup.50 and R.sup.51 each stand for a hydrogen atom or a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms or alicyclic hydrocarbon group having 4 to 10 carbon atoms; PA1 A.sup.1 is a hydrogen atom or a hydroxyl group; and PA1 n is 0, 1 or 2. PA1 R.sup.a1 stands for an acyl group having 2 to 7 carbon atoms or an alkoxycarbonyl group having 2 to 5 carbon atoms. PA1 R.sup.a2 stands for an alkyl group which may be substituted with a halogen atom, a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl (C.sub.1 -C.sub.2) alkyl group. PA1 m is 0, 1 or 2. PA1 R.sup.40 stands for a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an acyl group having 2 to 7 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, a tri(C.sub.1 -C.sub.7) hydrocarbon silyl group or a group capable of forming an acetal bond together with an oxygen atom attached to the R.sup.40. PA1 R.sup.12 stands for a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, alicyclic hydrocarbon group having 4 to 10 carbon atoms, aromatic hydrocarbon group having 6 to 10 carbon atoms or heterocyclic group having 1 to 9 carbon atoms; PA1 R.sup.1 stands for a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, alicyclic hydrocarbon group having 4 to 10 carbon atoms, aromatic hydrocarbon group having 6 to 10 carbon atoms or heterocyclic group having 1 to 9 carbon atoms; PA1 R.sup.302 stands for a hydrogen atom or a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, alicyclic hydrocarbon group having 4 to 10 carbon atoms or aromatic hydrocarbon group having 6 to 10 carbon atoms; PA1 R.sup.41 stands for an alkyl group having 1 to 4 carbon atoms, an acyl group having 2 to 7 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, a tri(C.sub.1 -C.sub.7) hydrocarbon silyl group or a group capable of forming an acetal bond together with an oxygen atom attached to the R.sup.41 ; and PA1 R.sup.52 stands for a hydrogen atom or a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms or alicyclic hydrocarbon group having 4 to 10 carbon atoms. PA1 Specific examples of the R.sup.12 include the groups referred to in the specific examples of the R.sup.1 described above in connection with the above-described formula (I). PA1 Specific examples of the R.sup.22 include the groups referred to in the specific examples of the R.sup.2 described above in connection with the above-described formula (I). PA1 Specific examples of the R.sup.302 include the groups referred to in the specific examples of the R.sup.3 described above in connection with the above-described formula (I). PA1 Specific examples of the R.sup.52 include the groups referred to in the specific examples of the R.sup.5 described above in connection with the above-described formula (I). PA1 R.sup.310 and R.sup.320, or R.sup.311 and R.sup.321 which may be the same or different from each other stand for a hydrogen atom, a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 9 carbon atoms, alicyclic hydrocarbon group having 4 to 10 carbon atoms or aromatic hydrocarbon group having 6 to 10 carbon atoms or a group wherein R.sup.310 and R.sup.320, or R.sup.311 and R.sup.321 are combined with each other to form an alicyclic hydrocarbon group having a four to ten-membered ring; and PA1 R.sup.42 stands for a hydrogen atom or a tri(C.sub.1 -C.sub.7) hydrocarbon silyloxy group. PA1 Specific examples of the R.sup.310 and R.sup.320, or R.sup.311 and R.sup.321 include the groups referred to in the specific examples of the R.sup.31 and R.sup.32 described above in connection with the above-described formula (I). PA1 Specific examples of the R.sup.42 include the groups referred to in the specific examples of the R.sup.4 described above in connection with the above-described formula (I). PA1 Preferred substituents of the R.sup.310 and R.sup.320 are respectively the same substituents as those of the R.sup.31 and R.sup.32, and preferred substituents of the R.sup.311 and R.sup.321 are respectively the groups described as the substituents of the R.sup.31 and R.sup.32 exclusive of the salt of a carboxylic acid.
and 5-(1-hydroxy-hydrocarbon)-4-substituted-2-cyclopentenone compounds represented by the following formula: ##STR3## wherein W' and Y' are the same as W and Y, respectively.
Further, the above publication also states that the above-described compounds are useful for treating a malignant tumor.
European Unexamined Patent Publication No. 0131441 (publication date: Jan. 16, 1985) discloses 5-alkylidene-2-halo-4-substituted-2-cyclopentenone compounds represented by the following formula: ##STR4## wherein Ra stands for a substituted or unsubstituted hydrocarbon having 1 to 12 carbon atoms or a substituted or unsubstituted phenyl group; Rb stands for a substituted or unsubstituted hydrocarbon having 1 to 12 carbon atoms; and X stands for a halogen atom,
and further discloses that the above-described compounds are similarly useful for treating a malignant tumor.
Further, it is also known that prostaglandin D compounds and prostaglandin J compounds, although different from the prostaglandin A compounds, are useful as an antitumor agent [see Japanese Unexamined Patent Publication (Kokai) No. 58-216155 and Proc. Natl. Acad. Sci., U.S.A., 81, 1317-1321 (1984)].
Japanese Unexamined Patent Publication (Kokai) No. 62-96438 discloses 4-hydroxy-2-cyclopentenone compounds represented by the general formula: ##STR5## wherein X stands for a hydrogen atom or a halogen atom; A and B stand for a hydrogen atom and a hydroxyl group, respectively, or are combined with each other to form a single bond; R.sup.J stands for a substituted or unsubstituted alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms; R.sup.K stands for a substituted or unsubstituted alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms; and R.sup.L stands for a hydrogen atom or a protecting group for a hydroxyl group, provided that R.sup.K is not 2-octenyl, 8-acetoxy-2-octenyl or 2,5-octadienyl,
and states that the above-described compounds are useful for the treatment of a malignant tumor.
It is commonly recognized that the metabolism of the bone of healthy persons is established by a good balance of the repetition of the absorption of bone by osteoclasts and the formation of bone by osteoblasts, and it is considered that the breaking of the balance between the absorption of bone and the formation of bone leads to diseases such as osteoporosis and osteomalalacia. Active vitamin preparations, calcitonin preparations, diphosphonic acid preparations, estrogen preparations, calcium preparations, etc. are used as a therapeutic agent for these diseases of bone. Nevertheless, although it has been reported that many of these preparations have a bone absorption inhibitory activity, there is no report clearly showing that they exhibit a bone formation accelerative activity. Further, since the effect of these preparations is not clear, the development of a preparation capable of more surely attaining the effect and having an activity through which the formation of bone by the osteoblasts is accelerated has been desired in the art.
Koshihara et al. reported in Biochemical Society of Japan (Preprints, 1988, p.767) that prostaglandin D.sub.2 has an activity through which the calcification by human osteoblasts is accelerated, and suggested that this activity is derived from the action of .sup.12 .DELTA.-prostaglandin J.sub.2, which is a decomposition product of the prostaglandin D.sub.2.